(Figure 3)
Drainage. Thoracentesis or paracentesis can be performed for symptomatic patients especially when mechanical ventilation is needed. However, drainage of large volumes of chyle can lead to fluid shifts, malnutrition, and immunocompromise due to loss of lymphocytes and immunoglobulins. In dwelling catheters can be a source for infection and can lead to a persistent chylous leak.
Shunting. Peritoneovenous or pleuroperitoneal shunts to drain chylous effusion or ascites have been utilized.[23, 24] Peritoneovenous shunts drain chylous ascites from the abdomen into the superior vena cava. Technical limitations include the size of the shunt relative to size of infant. Shunts complications include shunt occlusion, thrombosis, infection, disseminated intravascular coagulopathy, and need for shunt revision.[25] Shunting rarely provides a durable solution.
Pleurodesis. Obliteration of the potential space between the parietal and visceral pleura using chemical or a combination of chemical and mechanical pleurodesis has had some success in managing chylous effusions.[26] The procedure can be performed via tube thoracostomy or a thoracoscopic approach. Talc, povidone-iodine, and doxycycline are some of the agents used for pleurodesis.[26-28]
Surgical ligation. In preparation for surgical exploration due to chylous effusion or ascites, efforts to maximize finding the leak should be considered. Cessation of medical therapies to limit chyle production prior to intervention combined with pre-operative fat loading can prove helpful. It is not uncommon for surgeons to allow a patient to not only eat but encourage ingestion of a high fat diet to better identify the location of the lymphatic leak. Techniques described include 1 g of Sudan III dye mixed in 30 ml of milk given 6 hours preoperatively.[21, 29, 30] Intranodal, intradermal, or subcutaneous injection of lipophilic dyes prior to exploration can be used to facilitate visualization.[21] Thoracoscopic and laparoscopic approaches limit pain and can improve visualization; conversion to an open exploration is not perceived as a failure and is sometimes necessary for a thorough assessment. Suture ligation of the leaking lymphatic branch, thoracic duct, or cisterna chyli can be performed.[31] Fibrin glue and hemostatic or vicryl mesh are variably applied as reinforcement.[29] Lymphovenous anastomosis and lymphaticovenous bypass of the thoracic duct for the treatment of chylous leak in CCLA offers these patients a potential durable cure.[32, 33] Early results show that lymphaticovenous bypass does not ameliorate patients suffering with intestinal lymphangiectasia and protein losing enteropathy.[33] Drain placement at the time of surgical intervention is considered to manage any persistent lymphatic leak. The biggest risk of surgery is continued chylous leak.
Endolymphatic techniques. Thoracic duct or lymphatic channel embolization is a minimally invasive alternative to surgical ligation and can be successfully performed.[34, 35] It has several advantages over the surgical technique in being minimally invasive and image guided, but it can be challenging especially in premature infants and small children with small central ducts. Complete thoracic duct embolization usually involves placing microcoils and glue (n-butyl cyanoacrylate) into the thoracic duct. Selective embolization of the lymphatic channel can also be performed with coils and glue or glue alone. Selective embolization preserves thoracic duct flow which can be advantageous especially in patients with elevated central venous pressure. Lymphatic duct embolization has been successfully used in children with chylous effusions secondary to iatrogenic injury to the lymphatic duct.[35] Risks of lymphatic embolization include nontarget embolization to the periphery such as the lungs and stroke.[34]
In patients with neonatal chylothorax, Lipiodol®embolization and low-fat diet has recently been shown as effective treatment strategy.[7] In neonates with multicompartment disorders care should be taken not to occlude the central lymphatic ducts as this can lead to adverse outcomes. More selective and conservative management is favored in the neonatal population with diet and diuretics. Decompression strategies such as surgical lymphovenous anastomosis have been showing promise.
Nutritional management: Patients with high output lymphatic leak are at risk for severe nutritional deficiencies including vitamin D 25-hydroxy, zinc, copper and essential fatty acids.[36] While NPO, TPN with intralipids is necessary to prevent essential fatty acid deficiency.
Genetic sequencing: Many primary lymphatic malformations are due to sporadic somatic mutations in genes that regulate lymphangiogenesis. Gene variants often involve the VEGFC/VEGFR3 and PI3K/AKT/mTOR pathways. Additionally, some genetic syndromes are associated with abnormal lymphatic development including Down, Turner, Noonan and Cardiofaciocutaneous syndromes.[37] Identification of a genetic variant has implications for patient screening and management as potential therapeutic targets are discovered. With the identification of PI3K/AKT/mTOR variants within certain vascular malformations, their targeted inhibition is now the subject of several active clinical trials.[38] Sirolimus, an mTOR inhibitor further described below, has been utilized to improve function in patients with complex lymphatic anomalies. RAS/MAPK pathway variants have also been identified in complex lymphatic anomalies and represent a novel therapeutic target with MEK pathway inhibitors like trametinib.[39] Use of trametinib to treat symptomatic pediatric vascular anomalies currently is limited to the setting of a clinical trial or for compassionate use in the setting of a lesion with an identified RAS/MAPK pathway variant. Geneticists and genetic counselors are an increasingly important member of the multidisciplinary vascular anomalies team.
Sirolimus (Rapamune): mTOR inhibition has been increasingly utilized to improve function in symptomatic vascular anomalies. The mechanism of action is presumed to be the inhibition of an overactive PI3K/AKT/mTOR pathway, decreasing inappropriate cell growth and angiogenesis. Phase II trials have demonstrated efficacy of sirolimus in vascular anomalies including complex lymphatic anomalies.[40] Despite a paucity of data, sirolimus is used as a first-line pharmacotherapy agent in symptomatic Gorham Stout, Kaposiform lymphangiomatosis, and generalized lymphatic anomaly. Sirolimus’ efficacy in treating central conducting lymphatic anomaly is not known and is utilized as a secondary agent for refractory lymphatic leak. Although dosing practices vary, for use to treat pediatric vascular anomalies, we commonly initiate sirolimus at 0.8 mg/m2/dose given twice daily by mouth and further titrated to a serum trough level of 10-15 ng/ml.[40] Caution should be taken to dose reduce sirolimus in the newborn and premature infant with presumed immature drug clearance (consider starting dose of 0.2 mg/m2/dose given twice daily in the newborn or premature infant).[41] Concurrent Pneumocystis jiroveci pneumonia prophylaxis is recommended. Side effects include neutropenia, mucositis, peripheral edema, hypertension, hypertriglyceridemia, hypercholesterolemia, headache, and elevation of liver transaminases.